The prognostic significance of soluble NKG2D ligands in B-cell chronic lymphocytic leukemia

Soluble or membrane-anchored ligands of NKG2D and their receptor have a critical role in the elimination of tumor cells and disease progression. Plasma samples of 98 patients with B-cell chronic lymphocytic leukemia (CLL) were analyzed with specific ELISA systems for soluble major histocompatibility complex class I-related chains (sMICA and sMICB) and UL-16-binding proteins (ULBP1, 2, and 3). The flow cytometric analysis of MICA on CLL cells and natural killer group 2 member D (NKG2D) receptors on NK cells was performed after thawing of frozen peripheral blood lymphocytes of CLL patients (N = 51). Levels of sMICA, sMICB, and sULBP2 were significantly increased (P < 0.001) compared with 48 controls, whereas sULBP1 3 were not detectable in patients and controls. Levels of sMICA > 990 pg/ml (P = 0.014), sMICB > 200 pg/ml (P = 0.0001), and sULBP2 > 105 pg/ml (P < 0.0001) were associated with poor treatment-free survival (TFS). Neither MICA nor NKG2D expression could be related to clinical parameters. In multivariate analysis Binet stage (P = 0.002), sULBP2 (P = 0.002) and ZAP-70 (P = 0.002) were independent predictive factors for TFS. In patients with Binet stage A, sULBP2 levels > 105 pg/ml were strongly associated (P = 0.0025) with poor TFS. Our data show that soluble but not membrane-anchored NKG2D ligands or receptors are of prognostic significance in CLL. Moreover, sULBP2 seems to be useful to identify early-stage patients with risk of disease progression. Leukemia (2010) 24, 1152-1159; doi:10.1038/leu.2010.74; published online 29 April 2010